Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Molecular regulation of angiogenesis and lymphangiogenesis

Key Points

  • The angiogenic growth of blood-vessel capillaries involves sprouting and branching processes that are, in part, controlled by Notch signalling. Gradients of matrix-bound vascular endothelial growth factor A (VEGFA) and other navigational cues are recognized by specialized endothelial tip cells at the distal end of each sprout.

  • The recruitment of bone-marrow-derived monocytic cells to the perivascular space is an important process in adult angiogenesis.

  • The transcription factor prospero-related homeobox-1 (PROX1) is an important regulator of lymphatic endothelial cell differentiation. Sprouting, migration and proliferation of lymphatic endothelial cells is regulated by VEGFC and the VEGF receptor-3 (VEGFR3).

  • Arteriovenous identity is controlled by haemodynamic factors and, at least in some settings, genetic programmes. Such programmes involve the expression of Notch-pathway molecules in arterial endothelial cells whereas venous expression of these genes is actively suppressed by COUP-TFII, a member of the orphan nuclear receptor superfamily.

  • Pericytes and vascular smooth-muscle cells stabilize blood vessels and their incorporation into the vessel wall is an important part of the maturation programme.

  • Defective lymphangiogenic growth and compromised lymphatic endothelial cell identity appear to be interdependent. Known genes that are required for the differentiation of terminal lymphatics and collecting lymphatics as well as the formation of valves are forkhead box-c2 (FOXC2), angiopoietin-2 (ANG2) and ephrin-B2 (EFNB2).

Abstract

Blood vessels and lymphatic vessels form extensive networks that are essential for the transport of fluids, gases, macromolecules and cells within the large and complex bodies of vertebrates. Both of these vascular structures are lined with endothelial cells that integrate functionally into different organs, acquire tissue-specific specialization and retain plasticity; thereby, they permit growth during tissue repair or in disease settings. The angiogenic growth of blood vessels and lymphatic vessels coordinates several biological processes such as cell proliferation, guided migration, differentiation and cell–cell communication.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Origin of endothelial cells and assembly of the vasculature.
Figure 2: Angiogenic sprouting.
Figure 3: Guidance cues, adhesion molecules and cell-fate regulators that function both in the nervous system and in the vasculature.
Figure 4: Vasculogenic and intussusceptive growth of blood vessels.
Figure 5: Arteriovenous differentiation and mural-cell recruitment.
Figure 6: Developmental lymphangiogenesis.
Figure 7: Mural cell and lymphatic defects in mutant mice and human patients.

References

  1. 1

    Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653–660 (2003).

    Article  CAS  Google Scholar 

  2. 2

    Cueni, L. N. & Detmar, M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J. Invest. Dermatol. 126, 2167–2177 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. 3

    Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).

    Article  CAS  Google Scholar 

  4. 4

    Alitalo, K., Tammela, T. & Petrova, T. V. Lymphangiogenesis in development and human disease. Nature 438, 946–953 (2005).

    Article  CAS  Google Scholar 

  5. 5

    He, Y. et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 65, 4739–4746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Achen, M. G. & Stacker, S. A. Tumor lymphangiogenesis and metastatic spread — new players begin to emerge. Int. J. Cancer 119, 1755–1760 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Shibuya, M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J. Biochem. Mol. Biol. 39, 469–478 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nature Med. 9, 669–676 (2003).

    Article  CAS  Google Scholar 

  9. 9

    Ladomery, M. R., Harper, S. J. & Bates, D. O. Alternative splicing in angiogenesis: the vascular endothelial growth factor paradigm. Cancer Lett. 249, 133–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Nyberg, P., Xie, L. & Kalluri, R. Endogenous inhibitors of angiogenesis. Cancer Res. 65, 3967–3979 (2005).

    Article  CAS  Google Scholar 

  11. 11

    Lee, S., Jilani, S. M., Nikolova, G. V., Carpizo, D. & Iruela-Arispe, M. L. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J. Cell Biol. 169, 681–691 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Armulik, A., Abramsson, A. & Betsholtz, C. Endothelial/pericyte interactions. Circ. Res. 97, 512–523 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Bergers, G. & Song, S. The role of pericytes in blood-vessel formation and maintenance. Neuro-oncology 7, 452–464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Sainson, R. C. et al. Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J. 19, 1027–1029 (2005).

    Article  CAS  Google Scholar 

  15. 15

    Hellstrom, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007). One of several papers, which shows that endothelial sprouting and the selection of tip cells in the developing mouse retina are controlled by DLL4–Notch signalling.

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).

    Article  CAS  Google Scholar 

  17. 17

    Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006). References 16 and 17 demonstrate that blocking of DLL4-mediated signalling dramatically enhances angiogenic sprouting of tumour blood vessels. This process leads to compromised vessel formation, increased hypoxia and reduced tumour growth.

    Article  CAS  Google Scholar 

  18. 18

    Lobov, I. B. et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc. Natl Acad. Sci. USA 104, 3219–3224 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Suchting, S. et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl Acad. Sci. USA 104, 3225–3230 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Leslie, J. D. et al. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134, 839–844 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Siekmann, A. F. & Lawson, N. D. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445, 781–784 (2007). References 20 and 21 show that Notch signalling by Dll4 controls the angiogenic behaviour of endothelial cells in zebrafish intersegmental vessels.

    Article  CAS  Google Scholar 

  22. 22

    Ruhrberg, C. et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 16, 2684–2698 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Gerhardt, H. et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol. 161, 1163–1177 (2003). Characterization of the endothelial tip cell in the retina and the role of matrix-bound VEGF gradients in the guidance of vascular sprouts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Klagsbrun, M., Takashima, S. & Mamluk, R. The role of neuropilin in vascular and tumor biology. Adv. Exp. Med. Biol. 515, 33–48 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Neufeld, G. et al. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc. Med. 12, 13–19 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Pan, Q. et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11, 53–67 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Gerhardt, H. et al. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system. Dev. Dyn. 231, 503–509 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Eichmann, A., Makinen, T. & Alitalo, K. Neural guidance molecules regulate vascular remodeling and vessel navigation. Genes Dev. 19, 1013–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Kruger, R. P., Aurandt, J. & Guan, K. L. Semaphorins command cells to move. Nature Rev. Mol. Cell Biol. 6, 789–800 (2005).

    Article  CAS  Google Scholar 

  31. 31

    Neufeld, G. et al. Semaphorins in cancer. Front. Biosci. 10, 751–760 (2005).

    Article  PubMed  Google Scholar 

  32. 32

    Gu, C. et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307, 265–268 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Gitler, A. D., Lu, M. M. & Epstein, J. A. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev. Cell 7, 107–116 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Torres-Vazquez, J. et al. Semaphorin–plexin signaling guides patterning of the developing vasculature. Dev. Cell 7, 117–123 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Lu, X. et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179–186 (2004). Identification of UNC5B as a guidance receptor that controls vascular sprouting, which is reminiscent of the role of UNC5 molecules in the pathfinding of axonal growth cones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Wilson, B. D. et al. Netrins promote developmental and therapeutic angiogenesis. Science 313, 640–644 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Bedell, V. M. et al. roundabout4 is essential for angiogenesis in vivo. Proc. Natl Acad. Sci. USA 102, 6373–6378 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Park, K. W. et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev. Biol. 261, 251–267 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Suchting, S., Heal, P., Tahtis, K., Stewart, L. M. & Bicknell, R. Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J. 19, 121–123 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 442, 453–456 (2006). Beautiful demonstration that the lumen of endothelial cells in zebrafish intersegmental vessels is formed through the fusion of intracellular vacuoles. This is followed by intercellular fusion processes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Lubarsky, B. & Krasnow, M. A. Tube morphogenesis: making and shaping biological tubes. Cell 112, 19–28 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Davis, G. E. & Bayless, K. J. An integrin and Rho GTPase-dependent pinocytic vacuole mechanism controls capillary lumen formation in collagen and fibrin matrices. Microcirculation 10, 27–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    Parker, L. H. et al. The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation. Nature 428, 754–758 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. 44

    Mancuso, M. R. et al. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J. Clin. Invest. 116, 2610–2621 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

    Article  CAS  Google Scholar 

  46. 46

    Rafii, S., Lyden, D., Benezra, R., Hattori, K. & Heissig, B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nature Rev. Cancer 2, 826–835 (2002).

    Article  CAS  Google Scholar 

  47. 47

    Grunewald, M. et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124, 175–189 (2006). Demonstration that the recruitment of perivascular bone-marrow-derived circulating cells has an important role in adult angiogenesis.

    Article  CAS  Google Scholar 

  48. 48

    Djonov, V. & Makanya, A. N. New insights into intussusceptive angiogenesis. EXS 17–33 (2005).

  49. 49

    Torres-Vazquez, J., Kamei, M. & Weinstein, B. M. Molecular distinction between arteries and veins. Cell Tissue Res. 314, 43–59 (2003).

    Article  PubMed  Google Scholar 

  50. 50

    Heil, M., Eitenmuller, I., Schmitz-Rixen, T. & Schaper, W. Arteriogenesis versus angiogenesis: similarities and differences. J. Cell. Mol. Med. 10, 45–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Brouillard, P. & Vikkula, M. Vascular malformations: localized defects in vascular morphogenesis. Clin. Genet. 63, 340–351 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Bergan, J. J. et al. Chronic venous disease. N. Engl. J. Med. 355, 488–498 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Le Borgne, R., Bardin, A. & Schweisguth, F. The roles of receptor and ligand endocytosis in regulating Notch signaling. Development 132, 1751–1762 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Bray, S. J. Notch signalling: a simple pathway becomes complex. Nature Rev. Mol. Cell Biol. 7, 678–689 (2006).

    Article  CAS  Google Scholar 

  55. 55

    Limbourg, F. P. et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 111, 1826–1832 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Koo, B. K. et al. Mind bomb 1 is essential for generating functional Notch ligands to activate Notch. Development 132, 3459–3470 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 18, 901–911 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Krebs, L. T. et al. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 18, 2469–2473 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Gale, N. W. et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc. Natl Acad. Sci. USA 101, 15949–15954 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Duarte, A. et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 18, 2474–2478 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Nakajima, M. et al. Abnormal blood vessel development in mice lacking presenilin-1. Mech. Dev. 120, 657–667 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Himanen, J. P. & Nikolov, D. B. Eph receptors and ephrins. Int. J. Biochem. Cell Biol. 35, 130–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Murai, K. K. & Pasquale, E. B. 'Eph'ective signaling: forward, reverse and crosstalk. J. Cell Sci. 116, 2823–2832 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Williams, C. K., Li, J. L., Murga, M., Harris, A. L. & Tosato, G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107, 931–939 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Hainaud, P. et al. The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-Ephrin b2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res. 66, 8501–8510 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Mukouyama, Y. S., Gerber, H. P., Ferrara, N., Gu, C. & Anderson, D. J. Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin1-mediated positive feedback. Development 132, 941–52 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Stalmans, I. et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J. Clin. Invest. 109, 327–336 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Jakobsson, L. et al. Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis. Dev. Cell 10, 625–634 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Kwei, S. et al. Early adaptive responses of the vascular wall during venous arterialization in mice. Am. J. Pathol. 164, 81–89 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    le Noble, F. et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 131, 361–375 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    You, L. R. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005). Shows that the nuclear orphan receptor COUP-TFII suppresses the expression of components of the Notch pathway in venous endothelial cells. Because Notch signalling controls arterial differentiation, COUP-TFII is crucial for the specification of arteriovenous identity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Seo, S. et al. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Dev. Biol. 294, 458–470 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    LeCouter, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001).

    CAS  Google Scholar 

  77. 77

    Oliver, G. Lymphatic vasculature development. Nature Rev. Immunol. 4, 35–45 (2004).

    Article  CAS  Google Scholar 

  78. 78

    Oliver, G. & Alitalo, K. The lymphatic vasculature: recent progress and paradigms. Annu. Rev. Cell Dev. Biol. 21, 457–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Petrova, T. V. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21, 4593–4599 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Wilting, J. et al. Dual origin of avian lymphatics. Dev. Biol. 292, 165–173 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Sebzda, E. et al. Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev. Cell 11, 349–361 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Hong, Y. K. et al. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev. Dyn. 225, 351–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. 83

    Wigle, J. T. et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21, 1505–1513 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Wigle, J. T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769–778 (1999). Identification of PROX1 as the regulator of the first steps of lymphangiogenic growth in the mouse embryo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Harvey, N. L. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nature Genet. 37, 1072–1081 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Backhed, F., Crawford, P. A., O'Donnell, D. & Gordon, J. I. Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc. Natl Acad. Sci. USA 104, 606–611 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Abtahian, F. et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299, 247–251 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Karkkainen, M. J. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunol. 5, 74–80 (2004). Demonstration that the sprouting of PROX1-expressing lymphatic endothelial cells from embryonic veins is controlled by VEGFC.

    Article  CAS  Google Scholar 

  89. 89

    Baldwin, M. E. et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell. Biol. 25, 2441–2449 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Tammela, T., Enholm, B., Alitalo, K. & Paavonen, K. The biology of vascular endothelial growth factors. Cardiovasc. Res. 65, 550–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Ober, E. A. et al. Vegfc is required for vascular development and endoderm morphogenesis in zebrafish. EMBO Rep. 5, 78–84 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Dumont, D. J. et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946–949 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    Karpanen, T. et al. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am. J. Pathol. 169, 708–718 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Makinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Med. 7, 199–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Laakkonen, P. et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 67, 593–599 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Karpanen, T. et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 20, 1462–72 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Nagy, J. A. et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med. 196, 1497–1506 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Hong, Y. K. et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins. FASEB J. 18, 1111–1113 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Hirakawa, S. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201, 1089–1099 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Baluk, P. et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Invest. 115, 247–257 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Cursiefen, C. et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J. Clin. Invest. 113, 1040–1050 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Gale, N. W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411–423 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Tammela, T. et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105, 4642–4648 (2005).

    Article  CAS  Google Scholar 

  104. 104

    Makinen, T. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 19, 397–410 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Foo, S. S. et al. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124, 161–173 (2006).

    Article  CAS  Google Scholar 

  106. 106

    Fang, J. et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am. J. Hum. Genet. 67, 1382–1388 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Kriederman, B. M. et al. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum. Mol. Genet. 12, 1179–1185 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Petrova, T. V. et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Med. 10, 974–981 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Baluk, P., Hashizume, H. & McDonald, D. M. Cellular abnormalities of blood vessels as targets in cancer. Curr. Opin. Genet. Dev. 15, 102–111 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  Google Scholar 

  111. 111

    Betsholtz, C., Lindblom, P. & Gerhardt, H. Role of pericytes in vascular morphogenesis. EXS 115–125 (2005).

  112. 112

    Rolny, C. et al. Platelet-derived growth factor receptor-β promotes early endothelial cell differentiation. Blood 108, 1877–1886 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Allende, M. L. & Proia, R. L. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim. Biophys. Acta 1582, 222–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nature Rev. Mol. Cell Biol. 4, 397–407 (2003).

    Article  CAS  Google Scholar 

  115. 115

    Kono, M. et al. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J. Biol. Chem. 279, 29367–29373 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Liu, Y. et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106, 951–961 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Allende, M. L., Yamashita, T. & Proia, R. L. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102, 3665–3667 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Paik, J. H. et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 18, 2392–2403 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Luo, Y. & Radice, G. L. N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis. J. Cell Biol. 169, 29–34 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Chen, S. & Lechleider, R. J. Transforming growth factor-β-induced differentiation of smooth muscle from a neural crest stem cell line. Circ. Res. 94, 1195–1202 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Pipes, G. C., Creemers, E. E. & Olson, E. N. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 20, 1545–1556 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Miano, J. M. et al. Restricted inactivation of serum response factor to the cardiovascular system. Proc. Natl Acad. Sci. USA 101, 17132–17137 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Nishimura, G. et al. δEF1 mediates TGF-β signaling in vascular smooth muscle cell differentiation. Dev. Cell 11, 93–104 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Chang, D. F. et al. Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors. Dev. Cell 4, 107–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Bertolino, P., Deckers, M., Lebrin, F. & ten Dijke, P. Transforming growth factor-β signal transduction in angiogenesis and vascular disorders. Chest 128, 585S–590S (2005).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Goumans, M. J., Lebrin, F. & Valdimarsdottir, G. Controlling the angiogenic switch: a balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc. Med. 13, 301–307 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Ward, N. L. & Dumont, D. J. The angiopoietins and Tie2/Tek: adding to the complexity of cardiovascular development. Semin. Cell Dev. Biol. 13, 19–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    Thurston, G. Role of angiopoietins and Tie receptor tyrosine kinases in angiogenesis and lymphangiogenesis. Cell Tissue Res. 314, 61–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Thurston, G. et al. The anti-inflammatory actions of angiopoietin-1. EXS 233–245 (2005).

  130. 130

    Eklund, L. & Olsen, B. R. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp. Cell Res. 312, 630–641 (2006).

    Article  CAS  Google Scholar 

  131. 131

    Fiedler, U. et al. Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation. Nature Med. 12, 235–239 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Tait, C. R. & Jones, P. F. Angiopoietins in tumours: the angiogenic switch. J. Pathol. 204, 1–10 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. 134

    Kobayashi, H. & Lin, P. C. Angiopoietin/Tie2 signaling, tumor angiogenesis and inflammatory diseases. Front. Biosci. 10, 666–674 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Jones, N., Iljin, K., Dumont, D. J. & Alitalo, K. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nature Rev. Mol. Cell Biol. 2, 257–267 (2001).

    Article  CAS  Google Scholar 

  136. 136

    Saharinen, P. et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J. Cell Biol. 169, 239–243 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Le Bras, B. et al. VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain. Nature Neurosci. 9, 340–348 (2006).

    Article  CAS  Google Scholar 

  138. 138

    Storkebaum, E. et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8, 85–92 (2005). References 137 and 138 show that VEGF signalling is not confined to endothelial cells. VEGFC stimulates the proliferation of glial-cell precursors and VEGFA promotes the survival of motoneurons in an animal model of amyotrophic lateral sclerosis (ALS).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Li, D. Y. et al. Defective angiogenesis in mice lacking endoglin. Science 284, 1534–1537 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    McAllister, K. A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genet. 8, 345–351 (1994).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Poschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Matsui, K., Breitender-Geleff, S., Soleiman, A., Kowalski, H. & Kerjaschki, D. Podoplanin, a novel 43-kDa membrane protein, controls the shape of podocytes. Nephrol. Dial. Transplant. 14 (Suppl.1), 9–11 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Schacht, V. et al. T1α/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22, 3546–3556 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Jackson, D. G. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 112, 526–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Hirakawa, S. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am. J. Pathol. 162, 575–586 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Bamji, S. X. Cadherins: actin with the cytoskeleton to form synapses. Neuron 47, 175–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Tillet, E. et al. N-cadherin deficiency impairs pericyte recruitment, and not endothelial differentiation or sprouting, in embryonic stem cell-derived angiogenesis. Exp. Cell Res. 310, 392–400 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Tallquist, M. D., French, W. J. & Soriano, P. Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, e52 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Lindblom, P. et al. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 17, 1835–1840 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank several colleagues for collaboration and apologise to those whose work could not be cited owing to lack of space. Work in the authors' laboratories is supported by grants from Finnish Cancer Organizations, Sigrid Juselius Foundation, Academy of Finland, Novo Nordisk Foundation, European Union, National Institutes of Health, Louis Jeantet Foundation and Helsinki University Central Hospital.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

hereditary haemorrhagic telangiectasia

lymphoedema distichiasis

FURTHER INFORMATION

Ralf Adams's homepage

Kari Alitalo's homepage

Glossary

Angioblasts

Mesoderm-derived endothelial precursor cells that are not fully differentiated and retain some stem-cell properties.

Mesoderm

The cell layer in the vertebrate embryo that differentiates into mesenchyme, connective tissue, bone, muscle, the cardiovascular system and blood cells.

Mesenchyme

Mesoderm-derived embryonic connective tissue that generates bone, cartilage, fibroblasts, smooth muscle and other cell types.

Pericytes

Mesenchyme-derived cells that cover blood vessels and make direct contact with endothelial cells through numerous long processes. Pericyte–endothelial interactions involve adhesion molecules and ion channels, and stabilize the endothelium.

Filopodia

Slender cellular processes that extend from the front of migrating cells, attach to the surrounding matrix and help to move cells forward.

Mural cells

Cells of the outer vessel wall: pericytes and vascular smooth-muscle cells.

Axonal growth cones

Dynamic guidance structures at the distal end of growing nerve fibres that direct fibres to their appropriate targets and thereby promote the correct 'wiring' of the nervous system.

Pinocytosis

Uptake of extracellular liquid into cells in the form of membrane-coated vesicles.

Vascular smooth-muscle cells

Specialized smooth-muscle cells that form the outer layer of arteries, arterioles and larger veins. They provide blood vessels with mechanical stability that is due to their contractile properties and the deposition of matrix and elastic fibres.

Podocyte

Specialized, highly branched epithelial cell in the filtering units (glomeruli) of the kidney. Numerous podocyte foot processes cover the glomerular capillary basement membrane and thereby form a size-selective filtration barrier that is permeable to water, salts and glucose but retains macromolecules in the bloodstream.

Lymphoedema

Harmful interstitial liquid accumulation that is due to insufficient lymphatic drainage.

Neural crest cells

Ectodermal cells that delaminate from the neural tube in vertebrate embryos, migrate to various locations and contribute to different body structures such as the peripheral nervous system, bone and cartilage, skeletal and smooth muscle, or pigment cells in the skin (melanocytes).

Vascular stem cells

Stem cells that can differentiate into endothelial or mural cells in the blood vessel wall.

Haemangioblasts

Precursor cells that can differentiate into endothelial and haematopoietic cells.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Adams, R., Alitalo, K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8, 464–478 (2007). https://doi.org/10.1038/nrm2183

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing